title: Extracellular Nampt promotes macrophage survival via a nonenzymatic interleukin-6/STAT3 signaling mechanism.
abstract: Macrophages play key roles in obesity-associated pathophysiology, including inflammation, atherosclerosis, and cancer, and processes that affect the survival-death balance of macrophages may have an important impact on obesity-related diseases. Adipocytes and other cells secrete a protein called extracellular nicotinamide phosphoribosyltransferase (eNampt; also known as pre-B cell colony enhancing factor or visfatin), and plasma levels of eNampt increase in obesity. Herein we tested the hypothesis that eNampt could promote cell survival in macrophages subjected to endoplasmic reticulum (ER) stress, a process associated with obesity and obesity-associated diseases. We show that eNampt potently blocks macrophage apoptosis induced by a number of ER stressors. The mechanism involves a two-step sequential process: rapid induction of interleukin 6 (IL-6) secretion, followed by IL-6-mediated autocrine/paracrine activation of the prosurvival signal transducer STAT3. The ability of eNampt to trigger this IL-6/STAT3 cell survival pathway did not depend on the presence of the Nampt enzymatic substrate nicotinamide in the medium, could not be mimicked by the Nampt enzymatic product nicotinamide mononucleotide (NMN), was not blocked by the Nampt enzyme inhibitor FK866, and showed no correlation with enzyme activity in a series of site-directed mutant Nampt proteins. Thus, eNampt protects macrophages from ER stress-induced apoptosis by activating an IL-6/STAT3 signaling pathway via a nonenzymatic mechanism. These data suggest a novel action and mechanism of eNampt that could affect the balance of macrophage survival and death in the setting of obesity, which in turn could play important roles in obesity-associated diseases.
authors.affiliation: Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Yankun
authors.initials: Y
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dorweiler
authors.forename: Dongying
authors.initials: D
authors.lastname: Cui
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Connie W
authors.initials: CW
authors.lastname: Woo
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Brunkan
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wolberger
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Imai
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009537:Nicotinamide Mononucleotide / Q000737:chemistry; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000178:Acrylamides; D016207:Cytokines; D015850:Interleukin-6; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse